CONTROVERSY: MULTIPLE BIRTHS: WHAT DO PATIENTS WANT?

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1 CONTROVERSY: MULTIPLE BIRTHS: WHAT DO PATIENTS WANT? FERTILITY AND STERILITY VOL. 81, NO. 3, MARCH 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. The desire of infertile patients for multiple births Ginny L. Ryan, M.D., a Sunny H. Zhang, M.D., Ph.D., b Anuja Dokras, M.D., Ph.D., a Craig H. Syrop, M.D., a and Bradley J. Van Voorhis, M.D. a University of Iowa Roy J. and Lucille A. Carver College of Medicine and University of Iowa Hospitals and Clinics, Iowa City, Iowa Received February 4, 2003; revised and accepted May 19, Supported in part by a grant from Organon, West Orange, New Jersey. Reprint requests: Bradley J. Van Voorhis, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa (FAX: ; E- mail: brad-vanvoorhis@uiowa.edu). a Department of Obstetrics and Gynecology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, University of Iowa Hospitals and Clinics. b ObGyn Associates, P.C., Cedar Rapids, Iowa /04/$30.00 doi: /j.fertnstert Objective: To determine the proportion of infertile women who prefer a multiple birth over a singleton, patient characteristics associated with this desire, and patient knowledge about the risks of multiple births. Design: Prospective analysis. Setting: Academic university hospital based infertility center and private general gynecology clinic. Patient(s): Four hundred sixty-four female patients with infertility who presented for their initial visit. Main Outcome Measure(s): Demographic characteristics, infertility history, desire regarding multiple births, knowledge of the risks of multiple births, and goals of infertility evaluation and treatment were determined by using a 41-question survey. Univariate analysis was performed to assess patient characteristics associated with the desire for multiple births. Independent factors associated with this desire were assessed by multivariable logistic regression analysis. Result(s): 20.3% of women desired multiples over a singleton gestation. Nulliparity, lower family income, younger patient age, prior evaluation for infertility, longer duration of infertility, and lack of knowledge regarding risks of twin gestations were associated with this desire. Only nulliparity and lower family income were independently associated. Conclusion(s): A sizable minority of infertility patients prefers a multiple birth as their treatment outcome. Patient education may be an effective strategy to reduce the incidence of twin and higher-order multiple pregnancies. (Fertil Steril 2004;81: by American Society for Reproductive Medicine.) Key Words: Infertility, in vitro fertilization, multiple births, twins Between 1980 and 1997, the number of twin births in the United States increased 52% and the number of triplet and higher-order multiple births increased 404% (1). This increase was most marked among women 30 years of age or older. The related trends of older age at childbearing and increasing availability and use of assisted reproductive technologies (ART) in the United States are clearly associated with the increase in multiple births (1, 2). This trend promises to continue, as projections show that 5.4 million to 7.7 million women will experience infertility in 2025 (3) and many will undergo treatment using ART. The goal of ART has always been to achieve viable pregnancies with maximum efficiency. As a result, the rate of multifetal pregnancy has greatly increased. This trend is viewed by the medical community as a serious complication of ART, and the American Society for Reproductive Medicine has designated reduction in the incidence of multifetal pregnancy resulting from ART an essential goal for ART programs and their patients (4). Obstetrician/gynecologists and neonatologists are acutely aware of the risks inherent in pregnancies and deliveries involving multiple fetuses, as well as the increased morbidity and mortality among infants born of multifetal pregnancies (5, 6). Moreover, the economic effect on society and the economic and emotional stresses on families that are associated with raising twins, triplets, and more children are becoming increasingly apparent (5, 6). Proposed solutions to the alarming increase in the rate of multiple births have included use of minimal stimulation protocols and transfer of fewer embryos during IVF therapy. In our experience, however, patients do not always share their physicians concerns about multife- 500

2 tal pregnancy and have shown some resistance to these changes in clinical practice. Because patients are actively involved in clinical decision-making, understanding patient desires and knowledge about multiple birth is important. We surveyed a representative sample of patients with active infertility in eastern Iowa to determine their desire for multiple births as an outcome of infertility treatment. We sought to determine these patients knowledge about risks of multiple births and factors that predict a desire for a multiple gestation pregnancy. MATERIALS AND METHODS A survey containing 41 questions, some of which had multiple parts, was given to all new patients with infertility presenting to three clinical sites between October 1, 2001, and August 31, These sites were the Reproductive Endocrinology and Infertility Clinic at the University of Iowa Hospitals and Clinics, the In Vitro Fertilization Clinic at the University of Iowa Hospitals and Clinics, and a private practice gynecology clinic in Cedar Rapids, Iowa. The female partner was asked to fill out the questionnaire while waiting to be seen by the physician or nursing staff, before any clinical counseling had occurred. The questionnaire was collected on the same day, and nonresponders were noted. We included self-described infertility patients and those who had been referred with this diagnosis. Institutional review board approval was obtained before data collection. There were no conflicts of interest among the investigators. All questions were addressed to the female patients because their male partners did not always accompany them to their visit. Demographic characteristics, past obstetric history, and history of infertility evaluation and treatment were obtained. Women were asked about their expectations for their visit to the clinic. They were offered five goals for the visit, including gaining an understanding of the cause of their infertility, learning about natural methods of conceiving, learning about infertility treatments, starting infertility treatments, and finding out costs of treatment. They were then asked to indicate the importance of each on a 5-point Likert scale in which 0 represented not important and 4 represented extremely important. Using the same Likert scale, women were asked to indicate the importance of different factors, including efficacy, affordability, safety, interference with daily tasks, possibility of multiple births, possibility of a therapy causing pain, and use of a high-tech therapy, in their decision about infertility treatment. Treatment outcomes were ranked in order of preference. Possibilities included no child, singleton pregnancy (one child), twin pregnancy (two children), triplet pregnancy (three children), and quadruplet pregnancy or more (four or more children). Women were also asked whether they would consider multifetal reduction in a twin, triplet, quadruplet, or quintuplet pregnancy. The final set of questions determined women s knowledge of the risks of multiple births. Four true/false questions regarding risks of twins to mothers and their infants were administered. The same four questions were then posed regarding the risk of triplets. Specifically, patients were asked if they knew of the risk of preterm delivery, risks to the mother s health during pregnancy and delivery, risks of cerebral palsy and long-term health problems in the infant, and risk of death to the infant. The complete questionnaire is available on request. Our analysis focuses on women s desire for multiple births; their knowledge of the risks of such pregnancies; and the association between demographic, medical, and knowledge factors and the desire for multiples. Data were analyzed by using unpaired two-tailed t-tests and the Mann Whitney U test for continuous variables and the 2 or Fisher s exact test for categorical variables. Multivariable logistic regression analysis was done to assess independent demographic and medical factors associated with the desire for multiple births. Because previous evaluation for infertility and longer duration of infertility were collinear, only duration of infertility was included in the multivariable logistic regression analysis. P.05 was considered statistically significant. RESULTS Of 464 women, 449 (97%) returned the questionnaire. The remaining 15 patients declined to answer any of the questions. Not all of the 449 questionnaires were fully completed, and omitted questions were not included in our analysis. The mean age of respondents was 31 years, and the mean age of their partners was 33 years. Most women were well educated, and the majority had a family income greater than $50,000. Eighty-nine percent of women selected a religious affiliation. Almost all of the women had some health insurance, although only 27% had known full coverage for infertility treatment. Two thirds of women were nulliparous. The median duration of infertility was 33 months, and the majority of women had seen another physician about their infertility before their visit to our clinics (Table 1). When asked to indicate the relative importance of different goals for their first visit, women listed a desire to understand the cause of their infertility, to learn about treatments for infertility, and to start treatments equally as their most important goal. A desire to learn about natural methods of conception was ranked last by women. When asked to rank preferred treatment outcomes, 20.3% of patients listed twin, triplet, or quadruplet pregnancies as FERTILITY & STERILITY 501

3 TABLE 1 Demographic characteristics of the sample. Characteristic Data Mean age of patient (y) (range) 31 (19 47) Mean age of partner (y) (range) 33 (21 71) Level of education (%) Junior high school 1 High school/vocational school 27 College 56 Graduate 16 Annual family income (%) $25,000 5 $25,000 $50, $50,000 $100, $100, Religion (%) Catholic 30 Protestant 25 Jewish 1 Other 34 None 10 Insurance status (%) Yes 98 Full coverage for evaluation 35 Full coverage for treatment 27 Nulliparous (%) 65 If parous, mean no. of children 1.4 If parous, need for infertility treatment in 27 a previous pregnancy (%) Median (range) duration of infertility (mo) 33 (0 240) Seen by another physician for evaluation 77 of infertility (%) Clinic site (%) Reproductive endocrinology unit 68 IVF 21 Private gynecology center 10 preferable to a singleton pregnancy. Of these women, 94% ranked twins as their most desired outcome, 2% ranked triplets as their most desired outcome, and 4% ranked quadruplets or more as their most desired outcome. Among all women, avoidance of multiple births was a less important consideration at this stage of their infertility evaluation than were treatment efficacy, safety, affordability, and time to conception. With regard to twins, most women knew of the increased risk of preterm delivery and increased maternal risks during pregnancy and delivery. Less than half of the women knew of the increased risk of cerebral palsy and infant mortality. Knowledge of risks associated with triplet gestation was somewhat better, although only half of the women surveyed knew of the increase in infant mortality after a triplet pregnancy (Table 2). For the purposes of further data analysis, we split the sample into two groups on the basis of knowledge about TABLE 2 Patient knowledge of outcomes of multiple births. Condition about which patients knew Twin pregnancy (%) Triplet pregnancy (%) Increased risk of preterm delivery Increased maternal risks Increased risk of cerebral palsy Increased risk of infant mortality outcomes of twin gestation. Women were classified as less informed about the risk of twin pregnancy if they answered none, one, or two of the four questions correctly. Fifty-four percent of women were considered less informed. Women were classified as well informed if they answered three or four of the four questions correctly. This group included the remaining 46% of patients. The sample was similarly categorized on the basis of knowledge about risks of triplet pregnancy. Twenty-four percent of women were classified as less informed regarding these risks, whereas 76% were classified as well informed. In univariate analysis, the desire for multiple births was significantly associated with nulliparity, lower family income, younger patient age, previous evaluation for infertility, limited knowledge about outcomes of twin gestation, and longer duration of infertility (Table 3). The desire for multiple pregnancy was not associated with level of education, TABLE 3 Results of univariate analysis. Variable Patients desiring multiple birth (%) P value Parity Parous 11 Nulliparous Annual family income $25, $25, Knowledge of outcomes of twin gestation Well informed 16 Less informed Patient age 25 y y Previous evaluation of infertility Yes 23 No Duration of infertility 24 mo mo Ryan et al. Many infertile patients prefer multiples Vol. 81, No. 3, March 2004

4 TABLE 4 Desire for multiple births, in multivariable logistic regression analysis. Patient factor Odds ratio (95% CI) a P value Nulliparity (0 vs. 1 child) 2.71 ( ).002 Low family income ( $25,000/y vs. $25,000) 2.72 ( ).05 Duration of infertility ( 24 mo vs. 24 mo) 1.59 ( ).11 a Odds ratios were adjusted with the following variables in the model: parity, annual family income, duration of infertility, age, clinic site, and knowledge of outcomes of twin gestations. Age, clinic site, and knowledge were not independent risk factors for the desire for multiple-birth pregnancy. religious affiliation, knowledge about triplet gestation outcomes, insurance status, clinic site, or age of the male partner. After controlling for patient age, duration of infertility, clinic site, and knowledge about the risks of twin pregnancy, nulliparity and lower family income were the only factors independently associated with the desire for multiple birth pregnancies (Table 4). DISCUSSION One in five women listed a multiple birth as their most desired outcome of infertility treatment. Thus, a sizeable minority prefers the situation that the medical community is trying hard to avoid. Our study clearly shows that when making treatment decisions, women have many priorities that take precedence over avoidance of twin or triplet pregnancy. This finding supports our hypothesis that the increase in the rate of multiple births may be in part patient driven. Gleicher et al. (10) used a mailed questionnaire to assess the attitude of patients with infertility toward multiple births. They found that fear of multiple conception was rejected by 64% of surveyed patients and that 67% to 90% of couples desired conception of twins. Investigators concluded that the approach practiced world-wide to minimize multiple births does not concur with the desires and understanding expressed by patients with infertility problems and should be modified. However, the response rate of 15% may have biased the results. We found that a minority of patients was aware of all of the risks of a twin pregnancy. Awareness of the risks of triplet pregnancy was somewhat better. Lack of knowledge about outcomes of twin gestation was predictive of the desire for multiple births. The discrepancy between the knowledge about risks in the medical community compared with our sample knowledge is notable and suggests risk education may play an important role in counseling. Other patient factors that predicted the desire for multiple births were somewhat intuitive: nulliparity, longer duration of infertility, and previous evaluation for infertility. It seems reasonable that nulliparous couples who have been struggling with infertility for longer and have seen more physicians regarding this diagnosis may be more likely to want to meet their goal for family size as quickly as possible. In addition, couples inexperienced in the challenges of child rearing may be more likely to overestimate their ability to handle multiple infants and children. The last two patient characteristics significantly associated with the desire for multiples were not as intuitive: lower family income and younger patient age. We initially hypothesized that a higher family income and older patient age would be associated with the desire for multiple births, on the assumption that older patients would be more eager to complete their families with one conception and that wealthy couples would believe that they had the resources to care for twins, triplets, or more children. Instead, it may be that women with a lower family income are aware of the limits on their ability to pay for ART and want to maximize their results in the fewest possible treatment cycles. However, this explanation is not supported by our finding that insurance status was not associated with a desire for a multiple gestation pregnancy. Younger women may be more likely to underestimate the physical and economic resources needed to raise multiple children and are therefore less concerned about a multiple birth. On the other hand, older women may appreciate their relative lack of physical resources and actively avoid the possibility of multiple gestation. As the FIGO Committee for the Ethical Aspects of Human Reproduction and Women s Health summarized, multiple pregnancy has very serious implications for the mother and her offspring, for the family and the community, and for health service resources (5). Multiple gestation increases the risk of pregnancy-induced hypertension, preeclampsia, anemia, antepartum and postpartum hemorrhage, and maternal death (6). It is also clear that ART disproportionately contributes to the population of preterm, low-birth-weight, and very-low-birth-weight infants in the United States. It is estimated that in 1997, 3% of low-birth-weight infants and more than 4% of very-low-birth-weight infants were conceived with ART. These rates are six times the proportion that would be expected on the basis of the fre- FERTILITY & STERILITY 503

5 quency of the procedure. The increased rate of multiple births largely explains this phenomenon (7). Recent studies have shown an increased risk of neurologic disability, especially cerebral palsy, in children born after IVF, which is largely attributable to the high frequency of twin births (8). Review of data from the National Center for Health Statistics reveals that twins are 4 times more likely than singletons to die within the first month of life, and triplets are 10 times more likely to die in this time (1). Hospital costs for each twin or triplet infant can be twice or three times that of a singleton, and lifetime costs to the healthcare system and community may be 100 to 200 times that of a singleton (5, 9). Most of the factors associated in univariate analysis with the desire for multiple pregnancy are difficult or impossible to change. Such factors include parity, family income, age, and duration of infertility. Patient knowledge, however, can be addressed clinically. Despite the generally high socioeconomic status and education level of patients who present for treatment of infertility, physicians should not assume that these patients are fully aware of the risks of the treatment they are seeking. Furthermore, women may be unable to look beyond the immediate risks in the pregnancy and delivery to the long-term effect on their children s and family s lives. Bridging the knowledge gap between physicians and their patients should be a high priority for clinicians involved in women s healthcare as a whole, and particularly for those involved in infertility treatment. All patients with infertility require careful counseling about the chance of multiple births and the risks involved. Identifying patients with other risk factors for desiring multiple pregnancy, such as nulliparity and lower family income, can help physicians target those most in need of counseling. Clinicians must understand that a significant minority of patients with infertility desires multiple pregnancy and that some of the pressure to achieve multifetal pregnancies may come from patients. This understanding may facilitate appropriate counseling and bring the patient and clinician closer to a mutual agreement on the safest goals for infertility treatment. Future directions for research should include examination of the relationship between patient desire for multiple gestation and treatment decisions and outcomes. A difference in the number of embryos transferred, stimulation protocol selected, or number of twin or triplet deliveries would provide stronger support for our hypothesis that patient preference influences outcome. Surveys of the general population about their desires for and knowledge of multiple births and adverse outcomes will clarify whether our findings are unique to infertile women. The effect of education on patient knowledge and desires must also be explored, possibly in a follow-up survey after a counseling session or mailed educational campaign. Acknowledgments: The authors thank Dr. Ingrid Nygaard for statistical advice and thoughts on the study design; Drs. Vik Mahavni and John Geisler for assistance with statistical analysis and data management; Jill Blaine for developing the tools for data collection and management; and Organon, Inc., for sponsoring a portion of the study. References 1. Martin JA, Park MM. Trends in twin and triplet births: Natl Vital Stat Rep 1999;47(24): Grifo J. ASRM/SART statement on outcomes of ART. ASRM Bulletin 2002;4. Available at: ASRM web page: Press/sartoutcomes.htm1 3. Stephen EH, Chandra A. Updated projections of infertility in the United States: Fertil Steril 2002;70: ASRM Guidelines on number of embryos transferred. A Practice Committee Report. [Committee Opinion] November 1999; FIGO Committee for the Ethical Aspects of Human Reproduction and Women s Health. Ethical guidelines in the prevention of iatrogenic multiple pregnancy. Eur J Obstet Gynecol Reprod Biol 2001;96: Kinzler WL, Ananth CV, Vintzileos AM. Medical and economic effects of twin gestations. J Soc Gynecol Invest 2000;7: Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birthweight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346: Stromberg B, Dahlquist G, Ericson A, Finnstrom O, Koster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilization: a population-based study. Lancet 2002;359: Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF, Crowley WF. The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med 1994;331: Gleicher N, Campbell DP, Chan CL, Karande V, Rao R, Balin M, et al. The desire for multiple births in couples with infertility problems contradicts present practice patterns. Hum Reprod 1995;10: Ryan et al. Many infertile patients prefer multiples Vol. 81, No. 3, March 2004